Enabling strategies for step efficient syntheses

Abstract

The field of natural product total synthesis has reached the point where synthetic efficiency has become more important than merely defining a viable (yet less ideal) route to the target molecule. Synthetic efficiency is best represented by the number of steps it takes to finish the target molecule from readily available starting materials, as by reducing the number of steps, all other factors of synthetic efficiency are influenced positively. By comparing several total syntheses from the recent years, the most successful strategies for step efficient syntheses will be highlighted. Each synthesis will be presented using a color-coded synthetic flowchart, in which each step is categorized by a colored box. Five categories of transformations are defined and rated according to their synthetic value. Each class will be signified by different colors so that the reader can quickly see which parts of the synthesis are productive and those that are not.

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

“…[80,81] The examples mentioned here display one or more of these favorable characteristics and at the current level, it is fully realistic to target the preparation of several structural derivatives (e.g.f unctionalized molecular probes) of these natural products.A lthough no such investigations of zincophorin and SCH-351448 has been published to date,they may be forthcoming.A tl east there is little doubt that more extensive knowledge of structure-activity relationships (SAR) will not only facilitate the study of compound-specific biological activities (see Sections 3.1 and 3.2) but may also allow more broad conclusions on how carboxyl polyether ionophores perturb mammalian cells. [80,81] The examples mentioned here display one or more of these favorable characteristics and at the current level, it is fully realistic to target the preparation of several structural derivatives (e.g.f unctionalized molecular probes) of these natural products.A lthough no such investigations of zincophorin and SCH-351448 has been published to date,they may be forthcoming.A tl east there is little doubt that more extensive knowledge of structure-activity relationships (SAR) will not only facilitate the study of compound-specific biological activities (see Sections 3.1 and 3.2) but may also allow more broad conclusions on how carboxyl polyether ionophores perturb mammalian cells.…”

“…Thei mpressive achievements in the syntheses of zincophorin and SCH-351448 showcase how new methodology is ad river for increased efficiency.A lthough am easure of "efficiency" in ag iven synthesis is necessarily multidimensional, al ow overall step-count, high overall yield, and/or scalability can be considered important guideposts. [80,81] The examples mentioned here display one or more of these favorable characteristics and at the current level, it is fully realistic to target the preparation of several structural derivatives (e.g.f unctionalized molecular probes) of these natural products.A lthough no such investigations of zincophorin and SCH-351448 has been published to date,they may be forthcoming.A tl east there is little doubt that more extensive knowledge of structure-activity relationships (SAR) will not only facilitate the study of compound-specific biological activities (see Sections 3.1 and 3.2) but may also allow more broad conclusions on how carboxyl polyether ionophores perturb mammalian cells.…”

“…The impressive achievements in the syntheses of zincophorin and SCH‐351448 showcase how new methodology is a driver for increased efficiency. Although a measure of “efficiency” in a given synthesis is necessarily multidimensional, a low overall step‐count, high overall yield, and/or scalability can be considered important guideposts . The examples mentioned here display one or more of these favorable characteristics and at the current level, it is fully realistic to target the preparation of several structural derivatives (e.g.…”

Chemische Synthesen und chemische Biologie von Carboxylpolyether‐Ionophoren: Aktuelle Entwicklungen

“…[80,81] Die hier erwähnten Beispiele umfassen eine oder mehr dieser bevorzugten Merkmale,u nd auf dem aktuellen Niveau ist es gänzlich realistisch, die Herstellung diverser Strukturderivate (z. Obwohl eine Maßgabe fürd ie "Effizienz" einer spezifischen Synthese notwendigerweise mehrdimensional ist, kçnnen eine niedrige Gesamtstufenanzahl, hohe Gesamtausbeuten und/oder Skalierbarkeit als wichtige Parameter angesehen werden.…”

Synthesis of Quinolinone Alkaloids via Aryne Insertions into Unsymmetric Imides in Flow

“…MHz, DMSO-d6): δ = 172. 9,165.7,163.0,130.7,124.6,113.8,72.8,58.5,55.6 ppm;IR (neat) 3390,3291,3169,3094,3080,3014,2970,2942,2843,1769,1710,1685,1645,1618,1607,1574,1517,1458,1422,1394,1311,1254,1182,1146,1124,1025,849,809 N-(2-methoxyacetyl)-benzamide (4c) 4-Bromobenzamide (150 mg, 0.992 mmol, 1 equiv.) was dissolved in anhydrous pyridine (1.6 mL) and 2-methoxyacetyl chloride (0.181 mL, 1.99 mmol, 2 equiv.)…”